A variety of myocardial molecular alterations have suggested that genetic therapies may impact on cardiac disease. However, in order to utilize such genetic strategies to treat cardiac disease, safe and efficient methods for cardiac gene delivery must be developed. Importantly, to achieve alterations of heart function or structure, efficient gene delivery methods must be developed to transfect a majority of the myocardium. In this proposal, we investigate myocardial gene transfer in adult swine models employing cardiac surgery. The primary components of cardiac surgery may facilitate safer gene delivery since they result in an interruption and isolation of the coronary circulation. The central hypothesis is that global myocardial transgene expression can be safely achieved in adult swine utilizing adenoviral vector delivery during simulated cardiac surgery. The specific aims are: To define the optimal conditions for specific and efficient myocardial gene transfer in adult pigs utilizing common adenoviral vectors, delivered during simulated cardiac surgery, and to extend the duration of myocardial transgene expression, utilizing novel advanced generation vectors.